1. Field of the Invention
The present invention relates to a compound having the antiviral activity against C-type virus, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating liver disease caused by hepatitis C virus.
2. Description of the Related Art
Hepatitis C virus (HCV) is a RNA virus belonging to hepacivirus genus of Flaviviridae. This virus was first found in 1989 in USA.
Hepatitis C virus infection is developed by blood transfusion or is community-acquired. In particular, approximately 70% of its infection is caused by kidney dialysis according to the previous report. Once infected with hepatitis C virus, about 20% of the infected people develop acute hepatitis accompanied by liver cirrhosis within 5 years, which would be developed to liver cancer (Davis et al, New. Engl. J. Med., 321 (1989) 1501/Alter et al, Leonard et al., Current Perspective in Hepatology, (1989) p. 83). The high chronic infection rate is rare among RNA virus infections, and therefore such high rate indicates the hepatitis C virus is one of key mediators causing liver cancer. Recently, hepatitis C can be tested with almost every blood sample, so that the infection by blood transfusion has been significantly reduced. However, community-acquired hepatitis C infection has not been efficiently controlled, so its infection rate is very high, making it a world-wide issue.
In the meantime, unlike HBV, HCV is world-widely distributed and 1.5˜2% of the total world population are infected, according to the recent report. Once infected with HCV, it is most likely developed into chronic hepatitis. In particular, the chance of progressing to liver cirrhosis and liver cancer is significantly higher than HBV infection. HCV is a taxonomically different virus from HBV, and it belongs to a different virus family, so HCV cannot be prevented with HBV vaccine. Recently, interferon and ribavirin (anti-viral agent) are co-administered to treat HCV infection (Hayashi N., et al., J. Gastroenterol., 41, (2006), 17). However, response to these drugs are different according to the genotype and their medicinal effects are not so great. In addition, the side effects carried by the co-administration of both drugs are severe and the price of them is also very high. Therefore, it is requested to develop a novel and more efficient anti-HCV agent.
The anti-HCV agents, that have been developed to overcome the above disadvantages, display their pharmaceutical activities as the anti-HCV agents by blocking a specific stage of the life cycle of HCV.
The life cycle of HCV is as follows. Once HCV is adhered on the surface of the host cell, HCV invades in the host cell by endocytosis. HCV, invaded in the host cell, produces the precursor protein composed of approximately 3000 amino acid residues from its genomic RNA. Then, HCV reacts to NS3 encoded by the virus genome or signal peptidase of the host cell and NS4 protease to produce about 10 kinds of viral proteins such as capsid protein, envelope protein, NS3/NS4 protease, and NS 5B RNA polymerase, etc. The genomic RNA duplicated by NS 2B polymerase binds to capsid protein and envelope protein mediated by a-glucosidase to produce virus particles. The assembled HCV particles are released from the host cell (Manns M P., et al., Nat. Rev. Drug. Discov., 6, (2007), 991).
The anti-HCV agent is to inhibit the activity of HCV by blocking a certain stage of HCV life cycle, so that the agent is classified based on the life cycle of HCV, as RNA polymerase inhibitor type, protease inhibitor type, a-glucosidase inhibitor type, and other types. For example, the agents based on the activity to inhibit RNA polymerase such as MK-7009 (Merck) and R7128 (Pharmasset/Roche) are now in a phase I clinical trial, and such drugs as VCH-759 (Virochem), R1626 (Roche), and valopicitabine (Idenix) are in a phase II clinical trial. Among the protease inhibitors, ITMN-191 (R-7227, InterMune/Roche) is in a phase I clinical trial, TMC435350 (Medivir/Tibotec) is in a phase II clinical trial, and Boceprevir (SCH 503034, Schering) and Telaprevir (Vertex) are in a phase III clinical trial. In addition, the cyclophilin inhibitor DEBIO-025 (DEBIO) and the glucosidase I inhibitor celgosivir (MIGEBIX) are in a phase II clinical trial (Kronenberger B., et al., Clin Liver Dis., 12, (2008), 529).
However, the resistant virus that showed the resistance against the anti-HCV agents in clinical trial has already been reported. Thus, it is urgently requested to develop a novel anti-HCV agent having the activity to inhibit HCV with totally different mechanism from the conventional anti-HCV mechanism.
Thus, the present inventors studied on an anti-HCV agent that has less cytotoxicity but has excellent anti-viral activity against HCV. As a result, the inventors confirmed that the benzidine derivative had excellent anti-viral activity against HCV but hardly had cytotoxicity, leading to the completion of this invention.